Background: The primary cilium is a microtubule-based organelle that extends transiently from the apical cell surface to act as a sensory antenna. Initially viewed as a cellular appendage of obscure significance, the primary cilium is now acknowledged as a key coordinator of signaling pathways during development and in tissue homeostasis. Objectives: The aim of this review was to present the structure and function of this overlooked organelle,with an emphasis on its epididymal context and contribution to male infertility issues. Materials and Methods: A systematic review has been performed in order to include main references relevant to the aforementioned topic. Results: Increasing evidence demonstrates that primary cilia dysfunctions are associated with impaired male reproductive system development and male infertility issues. Discussion: While a large amount of data exists regarding the role of primary cilia in most organs and tissues, few studies investigated the contribution of these organelles to male reproductive tract development and homeostasis. Conclusion: Functional studies of primary cilia constitute an emergent and exciting new area in reproductive biology research.
Primary cilia (PC) are organelles that sense and respond to dynamic changes of the extracellular milieu through the regulation of target genes. By using the epididymis as a model system, we determined the contribution of primary cilia in the regulation of epithelial cell functions through the transduction of the Hedgehog (Hh) signaling pathway. Both Sonic (SHH) and Indian Hedgehog (IHH) ligands were detected in epididymal epithelial cells by confocal microscopy and found secreted in the extracellular space. Gene expression profiling preformed on ciliated epithelial cells indicated that 153 and 1052 genes were differentially expressed following treatment with the Hh agonist SAG or the Hh antagonist cyclopamine (Cyclo), respectively. Strikingly, gene ontology analysis indicated that genes associated with immune response were the most affected following Hh modulation. The contribution of epididymal PC to canonical Hh pathway transduction was validated by ciliobrevin D treatment, which induced a significant decrease in PC length and a reduction in the expression Hh signaling targets. Such findings bring us closer to a molecular understanding of the subtle immune balance observed in some epithelia, including the epididymis and the intestine, which are organs featuring both tolerance toward autoimmune spermatozoa (or commensal bacteria) and defense against pathogens.
Primary cilia play pivotal roles in embryonic patterning and organogenesis through transduction of the Hedgehog signaling pathway (Hh). While mutations in Hh morphogens impair the development of the gonads and trigger male infertility, the contribution of Hh and primary cilia in the development of male reproductive ductules, including the epididymis, remains unknown. From a Pax2Cre; Ift88fl/fl knock-out mouse model, we found that primary cilia deletion is associated with imbalanced Hh signaling and morphometric changes in the Wolffian duct (WD), the embryonic precursor of the epididymis. Similar effects were observed following pharmacological blockade of primary cilia formation and Hh modulation on WD organotypic cultures. The expression of genes involved in extracellular matrix (ECM), mesenchymal-epithelial transition, canonical Hh, and WD development was significantly altered after treatments. Altogether, we identified the primary cilia-dependent Hh signaling as a master regulator of genes involved in WD development. This provides new insights regarding the etiology of sexual differentiation and male infertility issues.
Objective: To identify circulating miRNAs associated with ovarian endometriosis (OMA), and to analyze candidate genes targeted by these miRNAs. Methods: Putative regulating miRNAs were identified through an original bioinformatics approach. We first queried the miRWalk 2.0 database to collect putative miRNA targets. Then, we matched it to a transcriptomic dataset of OMA. Moving from gene expression in the tissue to possible alterations in the patient plasma, a selection of these miRNAs was quantified by qRT-PCR in plasma samples from 93 patients with isolated OMA and 95 patients surgically checked as free from endometriosis. Then, we characterized the genes regulated by more than one miRNA and validated them by immunohistochemistry and transfection experiments on endometrial cell primary cultures obtained from endometrial biopsies of 10 women with and without endometriosis with miRNA mimics. Stromal and epithelial cells were isolated and cultured separately and gene expression levels were measured by RT-qPCR. Results: Eight miRNAs were identified by bioinformatics analysis. Two of them were overexpressed in plasma from OMA patients: let-7b-5p and miR-92a-3p (p < 0.005). Three miRNAs, let-7b and miR-92a-3p, and miR-93-5p potentially targeted KIAA1324, an estrogen-responsive gene and one of the most downregulated genes in OMA. Transfection experiments with mimics of these two miRNAs showed a strong decrease in KIAA1324 expression, up to 40%. Immunohistochemistry revealed a moderate-to-intense staining for KIAA1324 in the eutopic endometrium and a faint-to-moderate staining in the ectopic endometrium for half of the samples, which is concordant with the transcriptomic data. Discussion and Conclusion: Our results suggested that KIAA1324 might be involved in endometriosis through the downregulating action of two circulating miRNAs. As these miRNAs were found to be overexpressed, their quantification in plasma could provide a tool for an early diagnosis of endometriosis.
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